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Annals of Surgical Oncology

, Volume 21, Issue 13, pp 4164–4173 | Cite as

SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features

  • Tingting Li
  • Xiaoyun Liao
  • Paul Lochhead
  • Teppei Morikawa
  • Mai Yamauchi
  • Reiko Nishihara
  • Kentaro Inamura
  • Sun A. Kim
  • Kosuke Mima
  • Yasutaka Sukawa
  • Aya Kuchiba
  • Yu Imamura
  • Yoshifumi Baba
  • Kaori Shima
  • Jeffrey A. Meyerhardt
  • Andrew T. Chan
  • Charles S. Fuchs
  • Shuji OginoEmail author
  • Zhi Rong QianEmail author
Colorectal Cancer

Abstract

Background

Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear.

Methods

Using a database of 735 colon and rectal cancers in the Nurse’s Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1.

Results

SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34–0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35–0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13–0.95; P interaction = 0.035, for SMO and CIMP status).

Conclusions

Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed.

Keywords

Colorectal Cancer KRAS Mutation BRAF Mutation PIK3CA Mutation Hedgehog Signaling 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

Supported in part by USA National Institute of Health (NIH) [P01 CA87969 (to S. E. Hankinson), UM1 CA167552 and P01 CA55075 (to W. C. Willett), R01 CA137178 (to A.T.C.), P50 CA127003 (to C.S.F.), and R01 CA151993 (to S.O.)]; the Bennett Family Fund for Targeted Therapies Research; and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. PL was supported by a Harvard University Frank Knox Memorial Fellowship and a fellowship from the Chief Scientist Office, Scotland. A.T.C is a Damon Runyon Clinical Investigator. We would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR PA, RI, SC, TN, TX, VA, WA, and WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the article for publication; or the writing of the article.

Disclosure

No potential conflicts of interest exist.

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Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Tingting Li
    • 1
    • 2
  • Xiaoyun Liao
    • 1
  • Paul Lochhead
    • 1
  • Teppei Morikawa
    • 3
  • Mai Yamauchi
    • 1
  • Reiko Nishihara
    • 1
    • 4
  • Kentaro Inamura
    • 1
    • 5
  • Sun A. Kim
    • 1
  • Kosuke Mima
    • 1
  • Yasutaka Sukawa
    • 1
  • Aya Kuchiba
    • 1
    • 4
  • Yu Imamura
    • 1
  • Yoshifumi Baba
    • 6
  • Kaori Shima
    • 7
  • Jeffrey A. Meyerhardt
    • 1
  • Andrew T. Chan
    • 8
  • Charles S. Fuchs
    • 1
    • 9
  • Shuji Ogino
    • 1
    • 10
    • 11
    Email author
  • Zhi Rong Qian
    • 1
    Email author
  1. 1.Department of Medical OncologyDana-Farber Cancer Institute and Harvard Medical SchoolBostonUSA
  2. 2.Department of Geriatric GastroenterologyChinese PLA General HospitalBeijingChina
  3. 3.Department of PathologyUniversity of Tokyo HospitalTokyoJapan
  4. 4.Department of NutritionHarvard School of Public HealthBostonUSA
  5. 5.Laboratory of Human Carcinogenesis, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  6. 6.Department of Gastroenterological SurgeryKumamoto UniversityKumamotoJapan
  7. 7.Department of Oral PathologyKagoshima UniversityKagoshimaJapan
  8. 8.Gastrointestinal UnitMassachusetts General HospitalBostonUSA
  9. 9.Channing Division of Network Medicine, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  10. 10.Department of PathologyBrigham and Women’s HospitalBostonUSA
  11. 11.Department of EpidemiologyHarvard School of Public HealthBostonUSA

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